Film-forming composition; method of producing same and use for coating pharmaceuticals and foods and the like

ABSTRACT

A water dispersible polymeric film-forming particulate composition for use in coating pharmaceuticals and foods or the like, produced by freeze-drying an aqueous solution of water-soluble cellulose acetate as the film-forming polymer, a plasticizer, and optionally a pigment, is described. The product mixes readily with water to form an aqueous dispersion which is applied in the conventional manner to solid pharmaceutical forms.

This is a continuation-in-part of our U.S. patent application Ser. No.452,896, filed on Dec. 19, 1989 abandoned.

FIELD OF THE INVENTION

This invention relates to solid film-forming compositions for use incoating foods and pharmaceuticals and the like. More particularly, theinvention is concerned with such film-forming compositions which aredispersible in aqueous media.

BACKGROUND OF THE INVENTION

It is well known in the art to envelop solid pharmaceutical materials,tablets, granules and seeds, for example, in a film covering asprotection against oxidation, moisture, light, abrasion, rough handling,etc. The film should be free of roughness, irregularities, cracks ormottled colorations. Film smoothness is important as an aid inswallowing. A hard, shiny surface is desirable for an attractiveappearance. Of course, films and coating compositions for ingestion mustbe edible or physiologically compatible.

Film-forming compositions for coating pharmaceutical tablets preferablycontain as the film-forming element, a film-forming resinous material,either naturally occurring or synthetic. Normally, such compositions areapplied as a liquid coating formulation comprising a liquid carriermedium having dispersed or dissolved therein the film-formingcomponents. The liquid medium can be an organic solvent or water or acombination of both. Water is preferred owing to the risk of fire andtoxicity from organic solvents. Also having to comply with governmentalsafety standards pertaining to the transportation and handling ofindustrial chemicals is another minus factor against solvent use.

Generally speaking, application of the liquid coating formulation iseffected by spraying dry pharmaceutical forms in rotation in a coatingpan or in a fluidized air bed. After evaporation of the liquid medium,the film coated pharmaceuticals are recovered.

As a commercial product, liquid coating compositions are unsatisfactorybecause of the high transportation costs due to the weight of the liquidcarrier. Clearly, it is more practical and economical to ship coatingcompositions in dry form which can be reconstituted with the appropriatesolvent or liquid by the pharmaceutical customer. For this, a readilydispersible product is desirable which can be reconstituted by simplemixing or stirring.

It is known in the prior art to prepare dry coating formulations bygrinding a polymer powder with pigment particles and grinding themixture further to give a fine powder. However, when this is stirredinto water, the polymer tends to agglomerate resulting in a nonuniformdispersion which, unless permitted to solvate for an extended period oftime, gives poor coatings due to the presence of lumps and fish eyes.

An improved coating system is described in U.S. Pat. Nos. 4,543,370 and4,683,256 assigned to the Colorcon Corporation. According to thesedocuments, a pharmaceutical coating composition is produced by highintensity blending of polymer and pigment particles in the presence of aplasticizer. The resulting powder is mixed with water to form a coatingdispersion which is applied to tablets. On drying a uniform film is saidto be produced on the tablets. The coating can also be applied as asolution in an organic solvent.

The dry coating compositions of the Colorcon patents consist of separateindividual particles of pigment and polymer. Although the vigorous dryblending produces a fine powder, its heterogeneous nature is readilydiscernible under the scanning electron microscope.

SUMMARY OF THE INVENTION

A technique has now been found whereby solid, water dispersiblefilm-forming compositions which are of a homogeneous nature can berealized and the provisions and preparation of said compositionstogether with film coated pharmaceuticals and the like preparedtherewith constitutes the object and purpose of the invention.

The solid water dispersible film-forming compositions of the inventioncomprise freeze-dried particles of a film-forming water-solublecellulose acetate (WSCA) produced by freeze-frying an aqueous solutionof the polymer. Normally, the WSCA polymer solution will contain aplasticizer and pigment which subsequently appear homogeneouslydistributed in each of the freeze-dried particles derived from thepolymer solution. On mixing the homogeneous film-forming compositionwith water, there is produced an aqueous film-forming coating dispersioncomprising a solution of the WSCA in which are suspended anyparticulates such as pigments, colorants or the like. As understoodherein, the term "dispersion" includes the aqueous polymer solutionalone or in combination with suspended matter. The aqueous coatingdispersion can be applied to various articles such as a pharmaceuticalor food substrate. After drying, there remains a smooth homogeneous filmenvelope on the so-coated object.

The WSCA aqueous dispersions of the invention, prepared from thefreeze-dried WSCA, does not separate upon standing overnight beingsuperior in this respect to the aqueous dispersions formed from the dryblended polymer compositions of the aforecited U.S. Pat. Nos. 4,543,370and 4,683,256.

DETAILED DESCRIPTION OF THE INVENTION

In carrying out the invention, there is first prepared an aqueoussolution of WSCA to which is added plasticizer and optionally a pigment.After thoroughly blending the ingredients a homogeneous liquid isproduced. This generally contains a solids content of from about 5% toabout 40%, preferably about 10% to about 20%. Of the solids, about 50%to about 90%, preferably about 80% to about 90% is polymer; about 2% toabout 40%, preferably about 5% to about 10% is plasticizer and about 0%to about 20%, preferably about 5% to about 7.5% is pigment; allpercentages are on a 100% by weight basis.

The so prepared polymer solution is subjected to freeze-drying. In theprocedure employed herein, the polymer solution is frozen in bulk byplacing it in large trays followed by crushing or pulverizing of theresultant frozen mass to the desired particle size. The frozen WSCAparticles are then dried under vacuum with controlled heat to removemoisture and thereby produce dried polymer particles. Freeze-drying is awell known industrial technique for removing water and moisture from anaqueous substrate; see Chemical and Process Technology Encyclopedia byDouglas M. Considine, Editor-in-Chief; McGraw-Hill Book Company, pages523-527.

The freeze-dried (lyophilized) pulverulent film-forming composition ofthe invention consists mainly of highly porous, sponge-like particleshaving a bulk density of the order of about 100 mg/ml to 400 mg/ml.However, particle size is not critical except insofar as it affects therate of dispersion, larger particles requiring a longer time to undergodispersion than smaller particles.

The lyophilized powder in the above produced particle sizes is dispersedin water, using ordinary mixing or agitation means, such as a variablespeed propeller mixer, to give an aqueous, film-forming coatingcomposition. Mixing time to obtain a homogeneous dispersion is of theorder of about 15 to about 30 minutes. Exemplary particle size rangesfrom about 75 to 850 microns, preferably, about 60 to 250 microns.

Viscosity of the dispersion is a function of polymer, concentration andmolecular weight. By varying these parameters, dispersions having a widerange of viscosities can be realized. Viscosities (Brookfield RVT,Spindle #3 at 20 rpm) of the film-forming dispersions of the inventionare typically in the neighborhood of 300 to 700 cps. The compositionsare stable and do not settle out or agglomerate over a 24 hour period.

Microscopic examination of the freeze-dried particles of WSCA revealstheir homogeneous nature; none of the individual components making upthe particle can be discerned. It is believed that this homogeneity atthe particle level accounts for superior suspension stability of thedispersion and improved smoothness of the film coatings as compared withfilm coatings made from dry blends of polymer and pigment. Tests onpharmaceutical forms coated with the pigmented polymer showed excellentpreservation of cores against heat and humidity.

WSCA is a known material which is extensively documented in the patentand technical literature; see for instance, U.S. Pat. No. 3,482,011 toBohrer and assigned to Celanese Corporation. The polymer is available invarious viscosity grades from the Hoechst-Celanese Corporation,Charlotte, N.C. 28232. Films obtained with water-soluble celluloseacetate are clear, flexible, strong and durable.

WSCA employed herein is preferably a mixture of low and medium viscositytypes to provide a polymer blend from which aqueous polymer dispersioncan be prepared having the aforementioned viscosity in the 300 to 700cps. range.

Any of the pigments commonly used in making coating dispersions forcoating tablets and the like are suitable for inclusion in the dryfilm-forming compositions of the invention. Examples are FD&C and D&Clakes, titanium dioxide, magnesium carbonate, talc, pyrogenic silica,iron oxides, channel black and insoluble dyes. Also satisfactory arenatural pigments such as riboflavin, carmine 40, curcumin and annatto;pigments are optional ingredients which can be omitted.

Plasticizers for the WSCA in the coatings of the invention includepolyethylene glycols (PEG) having a molecular weight range of about 200to 4000, acetylated monoglyceride, glycerin, propylene glycol, triethylcitrate, acetyl triethyl citrate, triacetin; preferred plasticizers areglycerin and PEG 400.

The film-forming composition can be used to coat pharmaceuticals such astablets, seeds, granules, pellets, soft and hard gelatin capsules andthe like.

The aforementioned pharmaceutical dosage forms comprise drug classessuch as multivitamins, multivitamins with minerals, prenatal vitamins,vitamins A and D, B₁, B₂, B₆, B₁₂, and vitamin B complex with vitamin C.Additional drug classes include:

Analgesics--acetaminophen, aspirin, ibuprofen, ketoprofen and the like,indomethacin, naproxen, acetaminophen with codeine and acetaminophenwith propoxyphene napsylate.

Antibiotics--erythromycin, cephalosporins, etc.

Antiepileptics--phensuximide, phenytoin sodium and valproate sodium.

Antihistamines--chloropheniramine maleate, diphenhydraminehydrochloride, triprolidine hydrochloride, etc.

Cough and Cold Drugs--dextromethorphan hydrobromide, ephedrine sulfate,quaifenesin, phenylpropanolamine hydrochloride, promethazinehydrochloride, and pseudoephedrine hydrochloride.

Cardiovascular Drugs--captopril, chlorthiazide and hydrochlorthiazide,diltiazem, nadolol, papaverine hydrochloride, procainamidehydrochloride, propranolol hydrochloride, quinidine gluconate, quinidinesulfate, etc.

Electrolytes--potassium chloride.

Gastrointestinal Drugs--cimetidine, loperamide hydrochloride andranitidine.

Respiratory Drugs--albuterol sulfate, aminophylline, theophylline, etc.

The following nonlimiting examples in which all parts are by weightunless otherwise stated, illustrate the invention.

EXAMPLE 1 Dry Film-Forming Coating Powder (A) Formula

    ______________________________________                                                     Composition                                                      Components     Suspension  Solids   %                                         ______________________________________                                        WSCA*, low viscosity                                                                         2963.0      444.5    59.3                                      (15%)                                                                         WSCA, medium viscosity                                                                       2222.3      222.2    29.6                                      (10%)                                                                         PEG 400         33.3        33.3     4.4                                      Sepisperse ®, AP3027**                                                                    190.2       50.0     6.7                                      Water           591.2      --       --                                                       6000.0 g    750.0 g  100.0                                     ______________________________________                                         *Water-soluble cellulose acetate                                              **Sepisperse ® AP3027 is a commercial aqueous pigment dispersion          manufactured by Seppic, Paris, France. It contains 26.3% by weight pigmen     solids and 7.5% pigment solids were used based on total polymer solids.  

(B) Preparation

1. Low viscosity LV (15% by weight) and medium viscosity MV (10% byweight) water-soluble cellulose acetate (WSCA) solutions are preparedseparately.

2. The solutions are mixed (standard variable speed propellor-typemixer) for 60 to 120 minutes, covered and allowed to stand overnight toensure complete hydration of the polymer.

3. Appropriate amounts of each polymer solution are combined and mixedto achieve the desired polymer ratio. In the case of this example, thepolymer ratio of LV:MV is 2:1.

4. With continued mixing, water-soluble PEG 400 is added to the LV:MVWSCA polymer solution.

5. With continued mixing, Sepisperse^(R) aqueous pigment dispersion isadded to the plasticized polymer solution.

6. Water is added to the suspension to adjust the solids in the finalcomposition to 12.5% by weight and the composition is mixed thoroughly.

7. The composition is then lyophilized by conventional freeze dryingprocess.

(C) Film-Forming Coating Dispersion

The above obtained freeze-dried product (in powder form) can easily beredispersed in water to form a composition suitable for coating tabletsand the like.

Procedure for dispersing (mixing) the freeze-dried powder is as follows:

1. With a variable speed propellor-type mixer, freeze-dried powder isadded to water and mixed for 15 to 30 minutes to form a uniformdispersion.

2. In the case of this example, the concentration of solids in thecoating dispersion is 12.5% by weight.

3. Following conventional tablet coating procedures as described below,the dispersion from step 2. is applied to standard acetylsalicylic acid(ASA) tablets at a film loading of 3% based on the coated tablet weight.

    ______________________________________                                        Spray Coating Equipment                                                       Pan                   24" Accela-Cota                                         Baffles               4 straight & 4 mixing                                   Pump                  Masterflex 7562-10                                      Pump heads            Two 7015                                                Spray guns            Two SS 7310-1/4JAU                                      Fluid caps            1.0 mm                                                  Air caps              134255-45° SS                                    Spray Coating Conditions                                                                            Range                                                   Batch size (kg)       10                                                      Spray rate (ml/min/gun)                                                                             15-16                                                   Atomizing air (Bar)   1.5                                                     Gun distance (inches) 6 at 45°                                         Air temperature (°C.)                                                  Inlet                 60-75                                                   Exhaust               36-40                                                   Bed temperature (°C.)                                                                        32-35                                                   Pan rotation (rpm)    10                                                      Tablet bed warming (min. jogging)                                                                   10                                                      Total coating time (min.)                                                                           65-80                                                   Post drying                                                                   Inlet air temperature (°C.)                                                                  60                                                      Drying time (min.)    20                                                      Tablet weight gain (wt/wt %)                                                                        2.7-3.0                                                 ______________________________________                                    

EXAMPLE 2

The procedure of Example 1 was repeated except that glycerin was used asthe plasticizer. Comparable results were obtained.

We claim:
 1. A dry solid polymeric film-forming particulate compositionfor use in coating pharmaceutical and foods or the like comprisingwater-soluble cellulose acetate as the film-forming polymer havingincorporated therein, a plasticizer and optional pigment produced byfreeze drying an aqueous solution of the water-soluble cellulose acetatein which the total solids content of the solution is from about 5% toabout 40%, the solids containing about 50% to about 90% polymer, about2% to about 40% plasticizer selected from the group consisting ofpolyethylene glycol of molecular weight range of about 200 to about4000; triethyl citrate, acetyl triethyl citrate, triacetin and glycerinand about 0% to about 20% pigment the said film-forming compositionbeing capable of dispersal in an aqueous medium to give a water basedliquid coating composition.
 2. The composition of claim 1 wherein theplasticizer is glycerin.
 3. The composition of claim 1 wherein theplasticizer is polyethylene glycol of molecular weight
 400. 4. Thecomposition of claim 1 wherein the viscosity (Brookfield RVT Spindle #3at 20 rpm) of the water-soluble cellulose acetate is from about 300 to700 cps.
 5. A dry, film-forming particulate composition for use incoating pharmaceuticals and foods or the like comprising a film-formingwater-soluble cellulose acetate having a viscosity (Brookfield RVTSpindle #3 at 20 rpm) of about 300 to about 700 cps., havingincorporated therein a plasticizer selected from the group consisting ofglycerin and a polyethylene glycol having a molecular weight of fromabout 200 to about 4000 and a pigment, the said dry, film-formingparticulate composition being produced by freeze-drying an aqueoussolution containing about 80% to about 90% of the water-solublecellulose acetate; from about 5% to about 10% of the plasticizer andfrom about 5% to about 7.5% of the pigment and being capable ofdispersal in an aqueous medium to give a water based liquid coatingcomposition.
 6. A process for enveloping pharmaceuticals and foodproducts or the like in a protective film comprising the stepsof:forming an aqueous dispersion of a dry solid film-forming particulatecomposition containing water-soluble cellulose acetate as thefilm-forming polymer having incorporated therein a plasticizer selectedfrom the group consisting of polyethylene glycol of molecular weightrange of about 200 to about 4000; triethyl citrate, acetyl triethylcitrate, triacetin and glycering and optional pigment, the total solidscontent of the aqueous polymer solution being about 5% to about 40%, thesolids containing about 50% to about 90% polymer; about 2% to about 40%plasticizer and about 0% to about 20% pigment, and being produced byfreeze-drying, and aqueous solution of the water-soluble polymercontaining the plasticizer and pigment, and spraying said dispersion onthe form to be enveloped.
 7. The process of claim 6 wherein theplasticizer is selected from the class consisting of glycerin andpolyethylene glycol having a molecular weight of from about 200 to about4000.
 8. A process for enveloping pharmaceuticals and food products orthe like in a protective film comprising the steps:forming an aqueousdispersion of a dry solid film-forming composition having a solidscontent of from about 10% to about 20% comprising from about 80% toabout 90% of a film-forming water-soluble cellulose acetate; from about5% to about 10% of a plasticizer selected from the group consisting ofpolyethylene glycol of molecular weight range of about 200 to about4000; triethyl citrate, acetyl triethyl citrate, triacetin and glycerin,and from about 5% to about 7.5% of a pigment, and being produced byfreeze-drying an aqueous solution of the water-soluble cellulose acetatecontaining the plasticizer and pigment, and spraying said dispersion onthe form to be enveloped.
 9. The process of claim 8 wherein theplasticizer is selected from the class consisting of glycerin and apolyethylene glycol having a molecular weight of from about 200 to about4000.
 10. The process of claim 9 wherein the pigment is mixture of TiO₂and yellow iron oxide in the following formulation:

    ______________________________________                                                      Wt. Percent                                                     ______________________________________                                        Propylene Glycol                                                                              44.0                                                          Water           26.7                                                          HPMC            3.0                                                           Pigment Solids  26.3                                                                          100.0%                                                        ______________________________________                                    